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Objectives Although polymorphisms of the catechol-O-methyl transferase (COMT) gene have been implicated in altered pain sensitivity, results concerning the association between COMT gene polymorphisms and FM are equivocal. We assessed the associations between COMT single-nucleotide polymorphisms (SNP) and FM risk and symptom severity. Methods In total, 409 FM patients and 423 controls were enrolled. Alleles and genotypes at five positions [rs6269 (A>G), rs4633 (C>T), rs4818 (C>G), rs4680 (C>G) and rs165599 (A>G)] in the COMT gene were genotyped from peripheral blood DNA. Results Alleles and genotypes of the rs4818 COMT gene polymorphism were significantly associated with increased susceptibility to FM. The rs4818 GG genotype was more strongly associated with FM compared to the CC genotype (OR =1.680, 95% CI: 1.057, 2.672, P=0.027). Although allele and genotype frequencies did not differ among groups, the rs4633 CT genotype was not associated with the presence of FM following adjustment for age and sex (OR =0.745; 95% CI: 0.558, 0.995; P=0.046). However, no association was observed between clinical measures and individual COMT SNPs. In haplotype analysis, there was a significant association between ACG haplotype and FM susceptibility sex (OR =2.960, 95% CI: 1.447, 6.056, P=0.003) and the number of tender points (P=0.046). Conclusions This large-scale study suggests that polymorphisms of the COMT gene may be associated with FM risk and pain sensitivity in Korean FM patients. However, our results differed to those of previous studies, suggesting ethnic variation in COMT gene polymorphisms in FM. Disclosure of Interest None declared

Background Several pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, IL-8 and IL-15 are known to be critical in synovial inflammatory process in RA and successful results have been obtained in RA treatment with targeting pro-inflammatory cytokines including TNF-α, IL-1 and IL-6. Objectives This study sought to investigate the role of IL-33 and IL-6 in RA patients receiving IL-6 receptor inhibition therapy. Methods We analyzed the association of the IL-33 and IL-6 level with disease activity and serologic features in 83 patients with RA. We also measured the serum level of IL-33 and IL-6 before and after the administration of tocilizumab for 24 weeks in 40 patients. Results Serum IL-33 level showed significant correlation with RF (rho =0.660, p Serum IL-33 level significantly decreased after 24 weeks of IL-6 receptor inhibition in patients with RA (p Serum IL-6 levels were not significantly changed after 24 weeks of IL-6 receptor inhibition therapy (median 7.1 to 8.9 pg/mL, p=0.503). Changes of IL-6 levels were insignificant both in ACR20 responders and non-responders after 24 weeks of IL-6 receptor inhibition therapy. Baseline IL-6 levels were not different between ACR20 responders and non-responders. Conclusions The use of IL-6 receptor inhibitor decreased the serum level of IL-33 and this effect seems to be led by the responder group. IL-33 could be a useful indicator to monitor the response in IL-6 receptor inhibition therapy. Disclosure of Interest None declared

Background In recently, with development of biologic agents, RA patients increased the change of reaching remission. But some patients with normalization of inflammatory sign didn9t reach to clinical remission state after optimization of treatment. Objectives This study was performed to investigate the contribution of the more subjective versus the objective component of the DAS28 to response to treatment in RA patient. The secondary aim was to examine the factors associated with 6 month change in pain and EULAR response. Methods The DAS28-P was calculated (Subjective components of DAS28 relative to the total DAS28: DAS28-P=0.56*sqrt(TJC28) + 0.014*(VAS-GH)/0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.78 In(ESR) + 0.014*(VAS-GH)). From September 2011 to 2013, 462 new patients were included in this study. EULAR response was assessed after 6month of treatment. Results The mean age of the included patient was 54 years, and 79% were female. The mean DAS28 at baseline was 4.91±1.07 (range 3.21–8.56) and that at after 6 months of treatment was 3.29±1.28 (range 0.49–8.47). Good responders according to the EULAR criteria were 180 (38.9%), moderate responders 150 (32.4%) and none responders 96 (22.5%). The change of DAS28-P score at baseline and 6 month was significant only for good responders (0.43±0.11 versus 0.3±0.25, p Conclusions Our study showed that there are distinct RA patients with high DAS28-P, an index derived from subjective measures, who fails to respond adequately to treatment despite normalization of objective measures. Disclosure of Interest None declared

Objectives Endothelial PAS domain protein-1 (EPAS-1/HIF-2α), encoded by EPAS1 gene, is a catabolic transcription factor to regulate osteoarthritis (OA) cartilage destruction. In this study we examined whether microRNA-365 (miR-365) can regulate interleukin (IL)-1β-induced expression of catabolic factors in SW1353 cells and human articular chondrocytes via regulation of EPAS-1. Methods Total RNA was isolated from normal and OA cartilage tissues, human chondrocytes, and SW1353 cells. The level of miR-365 was quantified by TaqMan assay. The effects of miR-365 on expression of EPAS-1 and EPAS-1-modulated genes were measured by quantitative real-time polymerase chain reaction (qRT PCR), Western blot analysis, and enzyme-linked immunosorbent assay (ELISA). To examine the direct interaction of miR-365 with 39 untranslated region (UTR) of EPAS-1 mRNA, luciferase reporter assay was performed. Results The level of miR-365 in human OA cartilage was significantly decreased compared to normal cartilage. The overexpression of miR-365 significantly suppressed IL-1β-induced expression of EPAS-1 in both SW1353 cells and human articular chondrocytes. QRT PCR analysis using pharmacological inhibitors revealed that mitogen activated protein kinase and nuclear factor-κB signaling pathway was involved in IL-1β-induced miR-365 decrease and subsequent increase of EPAS-1 expression. Luciferase reporter assay using DNA construct containing binding site of miR-365 within 39UTR of human EPAS-1 mRNA demonstrated that the overexpression of miR-365 significantly suppressed IL-1β-induced up-regulation of EPAS-1. Furthermore, miR-365 overexpression significantly suppressed IL-1β-induced expression of catabolic factors, including cyclooxygenase-2, inducible nitric oxide synthase, and matrix metalloproteinase-1, -3 and -13, in SW1353 cells and human chondrocytes. Conclusions MiR-365 regulates IL-1β-stimulated catabolic effects in SW1353 cells and human chondrocytes via modulating the expression of EPAS-1. Disclosure of Interest None declared

Objectives Researchers continue to gather evidence that transient receptor potential vanilloid ( TRPV ) channels contribute towards pain signaling pathways. However, it is unknown whether polymorphisms of the TRPV gene are associated with fibromyalgia (FM). For the first time, we investigated the association between the polymorphisms of the TRPV2 and TRPV3 genes with FM susceptibility and the severity of the symptoms. Methods A total of 409 patients with FM and 423 controls were enrolled from 10 medical centers that participated in the Korean nationwide FM survey. The alleles and genotypes at three positions [rs3813768 (C>G), rs8121 (C>T), and rs1129235 (C>A)] in the TRPV2 gene, and two positions [rs7216486 (G>A) and rs395357 (C>T)] in the TRPV3 gene, were genotyped. Results The frequencies of the alleles and genotypes of individual TRPV2 and TRPV3 genes were not significantly associated with FM susceptibility. However, the GTA haplotype of TRPV2 showed a defense against FM susceptibility ( P =0.035). In addition, polymorphisms of TRPV3 were associated with symptom severity in FM patients. The single nucleotide polymorphism (SNP) rs395357 of TRPV3 was associated with the scores of the Brief Fatigue Inventory (BFI) ( P =0.017) in FM patients. Furthermore, haplotypes of TRPV3 were associated with the BFI and the SF-36 mental health summary scores ( P =0.036, respectively) Conclusions This study was the first to evaluate the associations of TRPV gene polymorphisms with FM. Our results suggest that certain TRPV2 haplotypes may have a protective role against FM, and also that some genotypes and haplotypes of TRPV3 contribute towards the symptoms of FM. Disclosure of Interest None declared

Background Xylosyltransferase-1 (XT-1), encoded by xylt1 gene, is an essential anabolic enzyme to catalyze the initial and rate-determining step in glycosaminoglycan chain synthesis. The effect of fibronectin fragments (FN-fs), generated by proteolytic cleavage of FN and known as damage-associated molecular pattern (DAMP) molecules, on cartilage metabolism was poorly characterized. Objectives In this study we examined 29-kDa amino-terminal fibronectin fragment (29-kDa FN-f)-mediated XT-1 expression mechanism and its signaling pathway, determining the role of 29-kDa FN-f in cartilage matrix synthesis. Methods Human articular chondrocytes were enzymatically isolated from articular cartilage and cultured in monolayer. In 29-kDa FN-f-stimulated chondrocytes, the relative levels of mRNA and protein for XT-1 were analyzed by real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis, respectively. In order to investigate the effects of 29-kDa FN-f on XT-1, human chondrocytes were transfected with small interfering RNAs (siRNAs) targeting TLR-2. Results The level of aggrecan and XT-1 in human osteoarthritis cartilage was significantly decreased compared to normal cartilage. XT-1 expression in cultured primary articluar chondrocytes showed a periodic oscillation in both mRNA and protein level. 29-kDa FN-f significantly suppressed the mRNA and protein levels of XT-1 at 14 h and 24 h, respectively. Knockdown of toll like receptor-2 (TLR-2) using small interference RNA revealed that the decrease of XT-1 expression by 29-kDa FN-f is mediated by TLR-2 signaling pathway. Inhibition of mitogen activated protein kinase (MAPK) and nuclear factor-κB (NF- κB) signaling pathway restored 29-kDa FN-f-inhibited XT-1 expression. In addition, reduction of XT-1 expression by 29-kDa FN-f- was associated with activation of activator protein 1 (AP-1) signaling pathway. Finally, 29-kDa FN-f enhanced the expression of Sp3 and inhibited the expression of Sp1. Knockdown and overexpression experiments confirmed that XT-1 expression was modulated by Sp3 and Sp1, which are ubiquitous transcriptional proteins and compete for the same DNA binding site. Conclusions These results demonstrated that 29-kDa FN-f plays a detrimental role in the regulation of cartilage extracellular matrix formation including XT-1 expression. Disclosure of Interest None declared

Background The disease activity scored based on 28 joints (DAS28) has been widely used in clinical practice and research studies of rheumatoid arthritis (RA). Objectives The objective of this study was to evaluate discordance between DAS28 based on erythrocyte sedimentation rate (ESR) versus C-reactive protein (CRP) in patients with RA. Methods From August to December 2011, 540 RA patients who visited 2 rheumatology clinics affiliated to Hallym University and had at least one DAS28 evaluation were examined. Results The mean age of the included patients was 53 years, and 82% were female. The mean duration of disease was 32.9±41.2 months. The mean DAS28-ESR was higher than DAS28-CRP (3.65 vs 3.44; p Conclusions There was discordance between the ESR based and CRP based DAS28, a situation that could affect clinical treatment decisions for RA patients. Disclosure of Interest None declared

Background Osteoarthritis (OA) is a degenerative disease characterized by the death of chondrocytes and the gradual loss of articular cartilage. Recently, transfer of a therapeutic protein into cells by the use of protein transduction domain (PTD) that targets the lipid bilayer directly has been tested in terms of therapeutic applications. The FK506-binding protein 12 kDa (FK506BP12) binds immunosuppressive drugs such as FK506 and modulates T cell activation via calcineurin inhibition. The anti-inflammatory properties of and immunomodulatory role played by FK506BP12, independent of FK506, have been demonstrated in several disease models Objectives In this study, we investigated the ability of PEP-1-FK506BP12, consisting of FK506BP12 fused to the PTD PEP-1 peptide, to suppress catabolic responses in primary human chondrocytes and in a mouse carrageenan-induced paw arthritis model. Methods Western blotting and immunofluorescence analysis showed that PEP-1-FK506BP12 efficiently penetrated chondrocytes and cartilage explants. Results In interleukin-1β (IL-1β)-treated chondrocytes, PEP-1-FK506BP12 significantly suppressed the expression of catabolic enzymes, including matrix metalloproteinases (MMPs)-1, -3, and -13; and cyclooxygenase-2, at both the mRNA and protein levels, whereas FK506BP12 alone did not. In addition, PEP-1-FK506BP12 decreased IL-1β-induced phosphorylation of the mitogen-activated protein kinase (MAPK) complex (p38, JNK, and ERK) and the inhibitor kappa B alpha. In the mouse model of carrageenan-induced paw arthritis, PEP-1-FK506BP12 suppressed both carrageenan-induced MMP-13 production and paw inflammation. Conclusions Thus, PEP-1-FK506BP12 may have therapeutic potential in the alleviation of OA progression. References S.R. Goldring, M.B. Goldring, The role of cytokines in cartilage matrix degeneration in osteoarthritis, Clin. Orthop. Relat. Res. (2004) S27-36. D.W. Kim, S.H. Lee, S.K. Ku, et al., Transduced PEP-1-FK506BP ameliorates corneal injury in Botulinum toxin A-induced dry eye mouse model, BMB Rep. 46 (2013) 124-129. S.Y. Kim, E.J. Sohn, D.W. Kim, et al., Transduced PEP-1-FK506BP ameliorates atopic dermatitis in NC/Nga mice, J. Invest. Dermatol. 131 (2013) 1477-1485. Acknowledgements This research was supported by a grant (A120960) from the Korean Health Technology RD Mid-career Research program grant (NRF-2009-0084569), and by Hallym University Research Fund. Disclosure of Interest None declared

Background Loss to follow-up can occur with many reasons, which influenced the outcomes of longitudinal cohort studies. Objectives To compare the characteristics of patients who lost to follow-up and patients who completed the 2 years of follow-up, and examine the associated factors for early loss to follow-up (ELTF). Methods The study subjects consisted of the KORONA cohort which is a multicenter longitudinal RA cohort. After excluding 1,119 patients who did not complete the 2 years of follow-up but still are actively participating, we divided the patients (n=4,257) into two groups; patients who lost to follow-up within 2 years (ELTF group), and patients who completed the 2 years of follow-up (FU group). Multivariate analysis was performed using the variables significant in univariate analyses and institutional factor. Institutions were divided in 3 groups based on the number of patients enrolled; A (largest) and C (smallest). Results ELTF group patients (n=1,674, 39%) were older (p=0.04) and less educated (p

Background Tocilizumab (TCZ) has been developed and investigated in several clinical trials for efficacy and adverse events in RA patients. But it remains to be investigated which biomarkers have early predictive values. Objectives To investigate predictive cytokines of TCZ therapy in rheumatoid arthritis (RA) patients with an inadequate response to disease-modifying antirheumatic drugs (DMARDs). Methods We collected sera as part of CWP-TCZ301, a 24-week, randomized, double–blinded trial of TCZ in RA patients with an inadequate response to DMARDs. Serum levels of cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-17A, IL-21 and IL-23 were determined by luminex multiplex analysis at baseline and after treatment (4, 12 and 24 weeks). IL-6 and soluble IL-6 receptor (sIL-6R) were measured by ELISA. Therapeutic response was evaluated by American College of Rheumatology 20% improvement (ACR20) in the TCZ group (n=47) and placebo group (n=48) after 24 weeks. Results Early withdrawal patients from the study were excluded in the evaluation. In TCZ group (n=40), 29 patients were ACR20 responders and 11 patients were non-responders after 24 weeks of treatment. Baseline serum levels of IL-17A were significantly lower in responders than in non-responders ( p

Background Although recent imaging studies of fibromyalgia (FM) have converged on a dysfunction of central pain processing as a primary pathophysiology of the disorder, microstructural alteration suggestive of abnormal synaptic transmission or functional activation has not been extensively examined. Objectives We aimed to investigate white matter integrity and its possible relationship with pain symptoms in female subjects with FM. Methods Nineteen FM patients and age-, and gender-, and education-matched 21 healthy controls (HCs) were included and underwent diffusion-weighted imaging. Group difference in white matter integrity, assessed via fractional anisotropy (FA), was investigated by applying tract-based spatial statistics. Results FM group showed a single cluster with lower FA in the left body of corpus callosum, which was found to be connected with the bilateral sensorimotor cortices, compared with HCs corrected for multiple comparisons ( P Conclusions In summary, the current study demonstrated that patients with FM had disrupted white matter microstructure in the body of corpus callosum associated with clinical pain intensity. Our results suggest that abnormal interhemispheric transfer might contribute to heightened pain perception and further strengthen the hypothesis of centrally augmented pain processing in FM. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4736

Background Fibromyalgia (FM) is characterized by chronic widespread pain. Patients are more sensitive to sensory stimulation regardless of type and modality, suggesting generalized dysfunction in sensory processing. Mismatch Negativity (MMN) is an event-related potential measuring pre-attentive auditory processing. Objectives The present study aimed to explore pre-attentive auditory processing, which might be affected as a part of generalized sensory processing dysfunction in FM by measuring MMN in FM patients and healthy controls (HC). Also we tried to find an association between MMN parameters and pain sensitivity in FM patients. Methods Auditory evoked fields were recorded using magnetoencephalography in 18 right-handed female FM patients and 21 age-, sex- and education-matched right handed HC during a duration-deviant auditory oddball paradigm (50-ms standard and 100-ms deviant tones). The magnetic counterpart of the MMN (MMNm) was obtained by subtracting the response to standard stimuli from the response to deviant stimuli. Peak latencies, amplitudes and directional asymmetry coefficient (AC) of the MMNm source were compared between two groups. Pressure pain threshold over the thenar and trapezius muscle was assessed for measuring pain sensitivity. Results FM patients exhibited reduced MMNm amplitude in the right hemisphere. Rightward asymmetry of MMNm was altered in FM patients indexed by lower AC values. Also, smaller right MMNm amplitude was associated with lower pressure pain threshold of thenar muscle in FM patients. Conclusions Pre-attentive auditory processing was compromised in FM indexed by reduced MMNm amplitude. This result suggests likelihood of generalized sensory processing dysfunction in FM. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4728

Background Interleukin-6 (IL-6), a proinflammatory cytokine, is thought to play a major pathological role in rheumatoid arthritis (RA). Tocilizumab is humanized anti IL-6 receptor monoclonal antibody which has been shown to improve signs and symptoms of RA. Objectives To investigate the efficacy and safety of tocilizumab in a Korean population. Methods This clinical trial was a 24-week phase III, randomized, double-blind, placebo-controlled, multicenter trial with two treatments arms and conducted from October, 2009 to October, 2010. The eligible patients had moderate to severe active RA, inadequately responding to MTX (or DMARDs). Tocilizumab at a dose of 8mg/kg or placebo were administered in a blinded manner, intravenously every 4 weeks, with stable dose of methotrexate (MTX) or other DMARDs. Results Total of 80 patients completed 24 week’s treatment with 40 patients in each treatment arm. At week 24, proportions of ACR 20, ACR 50, DAS28 remission and EULAR response were significantly higher in Tocilizumab group than in placebo group ( p p =0.0002, p =0.0002 and p p =0.0002, p =0.0055, respectively). Adverse drug reactions were more frequent in Tocilizumab group than in placebo group as follows; increased SGPT (21%), granulocytopenia (17%), leukocytopenia (15%), hypercholesterolemia (13%), pharyngitis (13%), and increased SGOT (10%). There were more incidences of serious adverse drug reactions in Tocilizumab group than in placebo group, but it was not significant ( p =0.0548). Conclusions In Korean population, administration of tocilizumab 8 mg/kg in combination with MTX (with or without other DMARDs) reduced RA activity significantly. Most of RA activity parameters including ACR 20, ACR 50, DAS 28 remission and EULAR response were achieved more frequently in Tocilizumab group than in placebo group. Tocilizumab was generally well tolerated since no safety issue was observed during the study. This study was financially supported by JW Pharmaceutical Co. (KFDA clinical trial-146). References Maini RN, et al. Arthritis Rheum. 2006;54(9):2817-29. Jones G, et al. Ann Rheum Dis. 2010;69(1):88-96. Disclosure of Interest None Declared

It is sometimes difficult to distinguish infection from disease flare in febrile patients with systemic lupus erythematosus (SLE). Chill, leucocytosis, and increased C reactive protein (CRP) are known to be markers favouring infection.1 Procalcitonin (PCT) is the precursor of calcitonin and is synthesised in the parafollicular C cells of the thyroid. Serum PCT increases in severe bacterial or fungal infection but does not increase, or increases only slightly, in viral infections.2 3 The purpose of this study was to evaluate the usefulness of serum PCT in febrile episodes of patients with SLE to distinguish infection from disease flare. We prospectively enrolled 19 patients with SLE with fever who were admitted to Seoul National University Hospital between October 1998 and April 1999. Fever was defined as an axillary temperature over 38°C. Eleven patients with inactive SLE were enrolled as controls. Blood of the febrile lupus patients was withdrawn three times: on the day of the hospital visit, and after 24 hours and 48 hours. Another sample was withdrawn two weeks after defervescence to control infection or because of a decrease in lupus activity. At the detection of fever, blood cultures and other necessary cultures were performed with complete blood count, Westergren erythrocyte sedimentation rate (ESR), CRP, serum anti-dsDNA, complements …